Pancreatic cancer is among the most deadly cancers in humans. It is diagnosed in more than 33,000 Americans a year with a five-year survival rate of only 5%. Pancreatic cancer is found often in late stage that is unresponsive to conventional cancer therapy, so it is imperative that new therapeutic strategies are developed to combat this devastating disease. Pancreatic cancer has some unique characteristics that make it so difficult to treat: The tumor mass is often composed of a large stromal component that is filled with fibrotic tissues and infiltrated immune cells, particularly those of myeloid lineages, such as macrophages and neutrophils. Although the precise functions of those immune cells within the tumor microenvironment remain to be fully determined, it is likely that they contribute to pancreatic tumorigenesis by providing cytokines and chemokines that in turn alter the microenvironment to enhance tumor growth and progression. Thus, it is important to develop new therapies for pancreatic cancer by functionally inhibiting those immune cells, including their mobilization from the bone marrow in response to signals released by the growing pancreatic tumor. In this regard, a chemokine termed PK2/Bv8 has been found in recent years to play a role in regulating the tumor microenvironment. CD11b+Gr1+ myeloid cells are the main source of PK2 production in response to stimulation by the cytokine GCSF. PK2 in turn regulates the bone marrow mobilization and possibly functions of myeloid cells via two G protein-coupled receptors. Based on this knowledge, we have conducted pilot experiments to test the ability of small molecule-based antagonists for PK2 to inhibit xenograft growth of human pancreatic cancer cells in nude mice and obtained promising preliminary results. To further explore the possibility that the PK2 antagonists can be developed into therapeutic agents for pancreatic cancer, we propose the following two Specific Aims: 1. Expand the test of anti-tumor effect of PK2 antagonists to a broad spectrum of human pancreatic cancer cells using xenograft tumor model; 2. Determine the efficacy of PK2 antagonists on the inhibition of spontaneous pancreatic tumor formation and progression in a K- Ras/p53 mouse transgenic model. Together these two complementary models will allow us to fully test the efficacy of anti-PK2 antagonists, alone or in combination with Gemcitabine, in inhibiting pancreatic tumorigenesis. Success of these two aims would lay the preclinical foundation for a possible clinical trial.